The present invention relates to pharmaceutical preparations for the treatment of diseases and disorders of the urinogenital tract.
Diseases and disorders of the bladder and urinary tract include cancers, infections, urinary incontinence, urethral syndrome, urethritis, female sexual dysfunction, and interstitial cystitis. These diseases and disorders may be treated by a variety of systemically administered pharmaceutical preparations. However, systemic delivery results in a number of side effects. For example, when oxybutynin hydrochloride is administered orally for the treatment of urinary incontinence, side effects including dizziness, blurred vision, dry mouth, and cardiovascular manifestations are experienced by patients. These side effects often limit the use of the formulation by the patients.
Local application of drugs for the treatment of bladder disorders, such as urinary incontinence, bladder cancer, and interstitial cystitis has been described in the literature. Intravesical administration of doxorubicin for bladder cancer, DMSO for interstitial cystitis, and oxybutynin hydrochloride for urinary incontinence have been shown to provide relief from symptoms without the side effects observed during systemic therapy. However intravesical administration is inconvenient and requires a trained technician to administer the drug formulation. Further, inserting and removing a catheter from a patient increases the risk of patient infection.
The term “urinary incontinence”, which refers to the inability to control urine flow, encompasses many different types of incontinence and results from different causes. For example, stress incontinence refers to when leakage of small amounts of urine during physical movement, such as coughing, sneezing, exercising. Urge incontinence generally refers to leakage of large amounts of urine at unexpected times, including during sleep.
Bladder emptying requires the maintenance of pressure in the bladder during the tonic phase of the contractile response. Bladder emptying and continence also depend upon the tonic phase of the contractile responses of the urethra. Thus, a defect in the ability of the bladder to sustain a contraction reduces the ability of the bladder to empty. Similarly, in women, if the urethra is unable to sustain increased tension during bladder filling, stress incontinence may result. Women depend upon urethral smooth muscle tension for continence to a much greater extent than men, where the prostate and better developed external sphincter add significantly to urethral tension and continence.
A second common cause of urinary incontinence is when the bladder contracts during bladder filling, i.e. hyperreflexia. These contractions are primarily due to neurogenic mechanisms involving the release of acetylcholine (herein referred to as “Ach”) and muscarinic-modiated bladder contractions.
One agent that has proven to be clinically effective in the treatment of urinary incontinence is oxybutynin. Oxybutynin relaxes the bladder by muscarinic inhibition and by direct relaxation of smooth muscle. Oxybutynin is one of the most widely prescribed oral medications for the treatment of stress incontinence (also referred to as “bladder instability”) and urge incontinence (see R. U. Anderson, et al., J. Urol., 161: 1809-1812 (1999); S. K. Gupta & G. Sathyan, J. Clin. Pharmacol., 39: 289-296 (1999); and J. W. Thüroff, et al., J. Urol., 145: 813-816 (1991)). However, its major disadvantages include its relatively short half-life and the resulting anticholinergic side effects. In many cases, patients do not follow their prescribed treatments due to the frequent dosing schedule and the side effects. In order to improve patient compliance, a long-acting preparation (once a day) was developed and tested (M. M. Goldenberg, Clin Ther, 21: 634-642 (1999); R. U. Anderson, et al., J. Urol., 161: 1809-1812 (1999);and E. Versi, et al., Obstet Gynecol., 95: 718-721 (2000)). Results of these studies demonstrate that the time-released preparation is as effective as the original preparation, but also produces the side effects associated with the administration of the original formulation (E. Versi, et al., Obstet Gynecol., 95: 718-721 (2000) and A. M. Comer & K. L. Goa, Drugs Aging, 16: 149-155 (2000)).
Intravesical instillation of oxybutynin has been evaluated. Brendler describes the intravesical administration of oxybutynin chloride for the treatment of dysfunctional bladders in a study of eleven patients with persistent urge incontinence and frequent side effects from the use of oral anticholinergic agents. (C. B. Brendler et al., J. Urology, 141 (6): 1350-52 (June, 1989)) Ten out of eleven patients reported improvement and became totally continent, and no side effects were observed. Similarly, Saito describes using a catheter to deliver an oxybutynin solution to patients suffering from urinary incontinence. (M. Saito et al., Neurology and Urodynamics 19: 683-88 (2000)) This method was effective, and the patients did not experience side effects.
Although this method of treatment can avoid the first pass metabolism and reduce systemic side effects (G. Buyse, et al., J. Urol., 160: 892-896 (1998); C. A. Masad, et al., J. Urol., 148: 595-597 (1992)), it is inconvenient and does not provide a method for continuous delivery. Further, intravesical administration requires a trained technician in a medical setting to administer the pharmaceutical preparation using a catheter or some other method of direct instillation into the bladder. Thus, intravesical administration prevents many patients from having daily access to such therapy. Moreover, the use of a catheter or other instrument increases the risk of infection caused by insertion and removal of the instrument and causes the patient discomfort.
A few researchers have begun to investigate vaginal delivery of anticholinergics, such as oxybutynin and propantheline bromide, to the bladder. Geraghty et al., Pharmaceutical Research 13(8): 1265-1271 (1996) a formulation containing monoolein and an antimuscarinic drug, either oxybutynin hydrochloride or propantheline bromide. Monoolein is a polar lipid which forms gels in the presence of water. Geraghty performed in vitro experiments to determine if the gel was an effective delivery system for the antimuscarinic drugs. The gel formulations demonstrated a sustained release of the antimuscarinic drugs for approximately 18 hours. Based on the release profile, it appeared that the drug diffused out of the gel. However, such results are not predictive of what would happen in vivo since the gel could degrade or the drug could be delivered systemically.
Schröder A et al., Urology 56 (6): 1063-1067 (2000) describes inserting a solid device which contained oxybutynin in the vagina of a rabbit. Though Schröder's insert was effective at reducing the systemic levels of oxybutynin, inserts are often uncomfortable for patients.
It is therefore an object of the present invention to provide formulations and methods of administration that are effective in treating diseases and disorders of the female urogenital system that also increase patient comfort and the likelihood that patients will follow their prescribed treatments.
It is a further object of the present invention to provide formulations and methods of administration that permit uptake of the drug in the affected area with minimal systemic side effects.